The mammalian immune system includes a complex array of organs, cells and soluble products of cells. Organs involved in the immune system include the bone marrow, spleen and lymph nodes; a wide variety of cells populate the immune system and this includes macrophages, granulocytes and T and B lymphocytes. Examples of soluble products produced by immune system cells include antibodies (produced by B lymphocytes) and lymphokines (produced by T-lymphocytes). The latter play an important role in regulating the immune system.
The basic functions of the immune system include:
(a) identification of substances or cells within the body to determine whether they are "self" or "non-self". PA1 (b) communication between cells to facilitate a response to "non-self" entities. PA1 (c) specific action on "non-self" substances or cells, for example specific lysis (dissolution) of a foreign cell. PA1 AIHA=autoimmune hemolytic anemia PA1 ATCC=American Type Culture Collection PA1 CEM=the lymphoblastic leukemic cell line CCRF-CEM (ATCC CCL 119) PA1 DAIT=direct anti-immunoglobulin test PA1 FCS=fetal calf serum PA1 .alpha.-MEM=minimum essential medium PA1 N=normal PA1 PBS=phosphate buffered saline PA1 RBC=red blood cells PA1 SAF=suppressor activating factor PA1 6-T=6-thioquanine PA1 (i) is secreted by a stable 6-thioguanine-resistant mutant of the lymphoblastoid cell line CEM. PA1 (ii) is non-mitogenic, and PA1 (iii) is non-cytotoxic. PA1 (iv) suppresses at least 90% of mitogen-induced T cell proliferation at a dilution of 10.sup.-6 but does not suppress mitogen-induced B cell proliferation at said dilution. PA1 (v) is contained in a high molecular weight protein, e.g. of about 110,000 dalton. PA1 (vi) exhibits maximum suppressor activity at physiological pH. PA1 (vii) is inactivated at 56.degree. C. PA1 (viii) suppresses mouse spleen cell proliferation to mitogenic stimulation with the same potency as it suppresses human peripheral blood lymphocyte proliferation to mitogenic stimulation. PA1 (ix) exhibits a greater suppressive effect on autoantibody production than an antibody production directed at foreign antigens (rat erythrocytes) in mice immunized with said rat erythrocytes.
The immune system is responsible for manifestations which include destruction of infecting organisms and the antoimmune reaction which is thought to be a malfunction of the system. It is now recognized that for various reasons and in view of various factors including aging, genetic makeup of the individual, viruses, thymic defects and hormones, the mammalian body may produce antibodies against parts of itself resulting in autoimmune diseases which include myasthenia gravis, autoimmune hemolytic anemia and rheumatoid arthritis.
Medical treatment of rheumatoid arthritis consists of the administration of drugs which may be classified as steroids, non-steroidal anti-inflammatory agents, gold salts and immuno-suppressive agents. Corticosteroids are used with caution, however, in view of serious side effects associated with long term use, including degenerative arthritis, hyperadrenocorticism and disruption of the pituitary-adrenal axis. Non-steroidal anti-inflammatory drugs such as aspirin, fenoprofen, ibuprofen and tolmetin are useful in long-term therapy provided that the side effects of high dosage, e.g. tinnitus, gastric upset and a decrease in platelet adhesiveness, are tolerated. Gold salts are associated with a high incidence of toxic side effects including dermatitis and aplastic anemia. Dramatic improvements in rheumatoid arthritis have been seen with immunosuppressive agents such as chlorambucil, cyclophosphamide, mercaptopurine and azathioprine. However, such drugs are associated with serious toxicity, may be teratogenic and may cause increases in lymphoma and infection. For these reasons, the routine use of immunosuppressive agents has been discouraged, see Chapter 26 entitled "Rheumatic Diseases" by K. H. Fye and K. E. Sack in the text "Basic and Clinical Immunology" by D. P. Stites et al. Lange Medical Publications, Los Altos, Calif. 94022 (1982).
It is an object of the present invention to provide an immunosuppressive therapy for mammals such as man afflicted with an autoimmune disease such as rheumatoid arthritis. A further object is a therapy which has few side effects and does not seriously affect the patient's ability to combat non-self antigents, e.g. infection.